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Cited by 382Inflammasome and immune disordersAtherosclerosis and Cardiovascular DiseasesLipoproteins and Cardiovascular Health

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Anti-inflammatory Action of Statins in Cardiovascular Disease: the Role of Inflammasome and Toll-Like Receptor Pathways

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Koushki, Khadijeh, Shahbaz, Sanaz Keshavarz, Mashayekhi, Kazem, Sadeghi, Mahvash, Zayeri, Zeinab Deris, Taba, Mahdieh Yousefi, Banach, Maciej, Al-Rasadi, Khalid, Johnston, Thomas P., Sahebkar, Amirhossein·2021·Clinical Reviews in Allergy & Immunology
DOI 10.1007/s12016-020-08791-9PMC PMC7985098
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Abstract

Atherosclerosis is one type of cardiovascular disease (CVD) in which activation of the NLRP3 inflammasome and toll-like receptor (TLR) pathways is implicated. One of the most effective treatments for atherosclerosis is the use of statin medications. Recent studies have indicated that statins, in addition to their lipid-lowering effects, exert inhibitory and/or stimulatory effects on the NLRP3 inflammasome and TLRs. Some of the statins lead to activation of the inflammasome and subsequently cause secretion of IL-1β and IL-18. Thus, these actions may further aggravate the disease. On the other hand, some statins cause inhibition of the inflammasome or TLRs and along with lipid-lowering, help to improve the disease by reducing inflammation. In this article, we discuss these contradictory studies and the mechanisms of action of statins on the NLRP3 inflammasome and TLR pathways. The dose-dependent effects of statins on the NLRP3 complex are related to their chemistry, pharmacokinetic properties, and danger signals. Lipophilic statins have more pleiotropic effects on the NLRP3 complex in comparison to hydrophilic statins. Statins can suppress TLR4/MyD88/NF-ĸB signaling and cause an immune response shift to an anti-inflammatory response. Furthermore, statins inhibit the NF-ĸB pathway by decreasing the expression of TLRs 2 and 4. Statins are cost-effective drugs, which should have a continued future in the treatment of atherosclerosis due to both their immune-modulating and lipid-lowering effects.

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Fig. 1 The roles of NLRPs and TLRs pathways in atherosclerosis pathophysiology. a At first, cholesterol and LDL deposit on vascular walls. Endothelial cells are stimulated through TLRs and resulted in ROS and PLA2 production. The ROS and PLA2 enzymes affected on accumulated LDL and cholesterol and produced ox-LDL and CCs. The ox-LDL and CCs ultimately, active endothelial cells and produce adherent molecules such as VCAM-1, which they evoke the monocular cells to the vascular wall. The ox-LDL and CCs as DAMPs are linked to NLRs and TLRs on phagocytized but they are resistant to macrophage lysosomal enzymes thus leads to the accumulation in macrophages and formats the foam cells which produce the wide range of pro-inflammatory cytokines. The IL-1β is one of the most important cytokines in atherosclerosis plaque and it has many roles such as increases the expression of adhesion molecules, which causes immune cells migration to the atherogenic site, smooth muscle cells proliferation, and MMPs activation, which lead to plaque rupture and obstructive thrombosis. b The stability of inflammation in atherosclerosis is required two signals; the initial signal is triggered via PRR receptors such as TLR, which activates NF-ĸB pathway that resulting in transcription of NLRP3 and pro-inflammatory cytokines such as pro-IL-1β, and the second signal is oligomerisation of activated NLRP3, and then call caspase-1 via Asc adaptor and eventually the formation of the inflammasome, which leads to proteolytic cleavage and activates pro-inflammatory cytokines such as pro-IL-1β and pro-IL-18 (abbreviations: CSR: cellular stress response is a macrophage scavenger receptor. IL-1βR: interleukin-1β receptor. LDL: low-density lipoprotein. OXLDL: oxidized LDL. NLRs: NOD-like receptor. NLRPs: Is an NLRs. TLR: toll-like receptor. VCAMs: vascular cell adhesion protein. ICAMs: intercellular adhesion molecule. MCP1: monocyte chemoattractant protein-1. ROS: reactive oxygen species. PLA2: phospholipases A2. CCs: cholesterol crystals. DAMPs: damage-associated molecular patterns. MMPs: matrix metalloproteinases. PRR: pattern recognition receptors. NF-ĸB: nuclear factor kappa-light-chain-enhancer of activated B cells. Asc: apoptosis-associated speck-like protein containing a CARD. MAPKs: mitogen-activated protein kinase. TNF-α: tumor necrosis factor-α. IL: interleukin. Lox-1: lectin-type oxidized LDL receptor-1. MyD-88: myeloid differentiation primary response-88)
Fig. 1 The roles of NLRPs and TLRs pathways in atherosclerosis pathophysiology. a At first, cholesterol and LDL deposit on vascular walls. Endothelial cells are stimulated through TLRs and resulted in ROS and PLA2 production. The ROS and PLA2 enzymes affected on accumulated LDL and cholesterol and produced ox-LDL and CCs. The ox-LDL and CCs ultimately, active endothelial cells and produce adherent molecules such as VCAM-1, which they evoke the monocular cells to the vascular wall. The ox-LDL and CCs as DAMPs are linked to NLRs and TLRs on phagocytized but they are resistant to macrophage lysosomal enzymes thus leads to the accumulation in macrophages and formats the foam cells which produce the wide range of pro-inflammatory cytokines. The IL-1β is one of the most important cytokines in atherosclerosis plaque and it has many roles such as increases the expression of adhesion molecules, which causes immune cells migration to the atherogenic site, smooth muscle cells proliferation, and MMPs activation, which lead to plaque rupture and obstructive thrombosis. b The stability of inflammation in atherosclerosis is required two signals; the initial signal is triggered via PRR receptors such as TLR, which activates NF-ĸB pathway that resulting in transcription of NLRP3 and pro-inflammatory cytokines such as pro-IL-1β, and the second signal is oligomerisation of activated NLRP3, and then call caspase-1 via Asc adaptor and eventually the formation of the inflammasome, which leads to proteolytic cleavage and activates pro-inflammatory cytokines such as pro-IL-1β and pro-IL-18 (abbreviations: CSR: cellular stress response is a macrophage scavenger receptor. IL-1βR: interleukin-1β receptor. LDL: low-density lipoprotein. OXLDL: oxidized LDL. NLRs: NOD-like receptor. NLRPs: Is an NLRs. TLR: toll-like receptor. VCAMs: vascular cell adhesion protein. ICAMs: intercellular adhesion molecule. MCP1: monocyte chemoattractant protein-1. ROS: reactive oxygen species. PLA2: phospholipases A2. CCs: cholesterol crystals. DAMPs: damage-associated molecular patterns. MMPs: matrix metalloproteinases. PRR: pattern recognition receptors. NF-ĸB: nuclear factor kappa-light-chain-enhancer of activated B cells. Asc: apoptosis-associated speck-like protein containing a CARD. MAPKs: mitogen-activated protein kinase. TNF-α: tumor necrosis factor-α. IL: interleukin. Lox-1: lectin-type oxidized LDL receptor-1. MyD-88: myeloid differentiation primary response-88)CC BY · PubMed Central
Fig. 2 The NLRs and TLRs families’ structure. a The NLR families are divided into five sub-families including NLRA, NLRB, NLRC, NLRP, and NLRX. The symbols and structures of the 22 members are shown. b Cell surface and intracellular TLRs and their ligands. TLRs are divided into two groups based on their cellular localization. TLRs 1, 2, 4–6, and 11 localize to the cell surface and TLRs 3 and 7–9 reside at endosomal compartments. Cell membrane TLRs respond to microbial membrane antigens such as LPS, whereas endosomal TLRs recognize the virus and bacteria-derived nucleic acids (abbreviations: NLR: Nod-like receptor. CARD: caspase recruitment domain. PYD: pyrin domain. NACHT: nucleotide-binding and oligomerization domain. LRR: leucine-rich repeat. BIR: baculoviral inhibition of apoptosis protein repeat domain. NAD: NACHT-associated domain. AD: acidic transactivation domain. FIIND: domain with function to find. TLR: toll-like receptor. ssRNA: single-strand RNA. dsRNA: double-strand RNA. CpG DNA: CpG oligodeoxynucleotide. LPS: lipopolysaccharides)
Fig. 2 The NLRs and TLRs families’ structure. a The NLR families are divided into five sub-families including NLRA, NLRB, NLRC, NLRP, and NLRX. The symbols and structures of the 22 members are shown. b Cell surface and intracellular TLRs and their ligands. TLRs are divided into two groups based on their cellular localization. TLRs 1, 2, 4–6, and 11 localize to the cell surface and TLRs 3 and 7–9 reside at endosomal compartments. Cell membrane TLRs respond to microbial membrane antigens such as LPS, whereas endosomal TLRs recognize the virus and bacteria-derived nucleic acids (abbreviations: NLR: Nod-like receptor. CARD: caspase recruitment domain. PYD: pyrin domain. NACHT: nucleotide-binding and oligomerization domain. LRR: leucine-rich repeat. BIR: baculoviral inhibition of apoptosis protein repeat domain. NAD: NACHT-associated domain. AD: acidic transactivation domain. FIIND: domain with function to find. TLR: toll-like receptor. ssRNA: single-strand RNA. dsRNA: double-strand RNA. CpG DNA: CpG oligodeoxynucleotide. LPS: lipopolysaccharides)CC BY · PubMed Central
Fig. 3 The effects of statins in atherosclerosis (a) and the immune system (b) (abbreviations: HMG-CoA: 3-hydroxy-3-methyl-glutaryl-coenzyme A. MMP: matrix metalloproteinases. ROS: reactive oxygen species. MHC-II: major histocompatibility complex-II. LDL: low-density lipoprotein)
Fig. 3 The effects of statins in atherosclerosis (a) and the immune system (b) (abbreviations: HMG-CoA: 3-hydroxy-3-methyl-glutaryl-coenzyme A. MMP: matrix metalloproteinases. ROS: reactive oxygen species. MHC-II: major histocompatibility complex-II. LDL: low-density lipoprotein)CC BY · PubMed Central
Fig. 4 The effects of statin on NLRP3 inflammasome and TLRs pathways. It appears that the effects of statins on NLRP3 complex are related to chemistry and pharmacokinetics features. Lipophilic statins have more pleiotropic effects on NLRP3 complex compare than hydrophilic statins. In the other hand, statins with inhibition of the mevalonate pathway, the protein prenylation or lipidation, and decreases cholesterol production caused reduce TLR agonists and suppressing TLR4/MyD88/NF-ĸB pathway. Also, statins inhibit NF-ĸB through reduce MAPKs phosphorylation and stabilized IKB-α as an NF-ĸB inhibitor. Statins inhibit expression of LOX-1 receptor; therefore, they could inhibit the inflammation of NLRP3 through LOX-1/NF-ĸB pathway. The diabetes basic risk, metabolic syndrome, genetic, and lifestyle could promote NLRP3 inflammasome in presence statins. The statin could decrease the expression of TLRs 2 and 4, so suppressed NF-ĸB activity. At the genetic and molecular level, the TLR4 D299G polymorphism contributes in less susceptibility to cardiovascular disorders and increase response to statin therapy; also, statin therapy has a positive effect on miRNAs levels which affected on TLRs and negatively regulated TLR4 (abbreviations: LDL: low-density lipoprotein. OXLDL: oxidized LDL. NLRP3: Is a NLRs. CCs: cholesterol crystals. NF-ĸB: nuclear factor kappa-light-chain-enhancer of activated B cells. Asc: apoptosis-associated speck-like protein containing a CARD. MAPKs: mitogen-activated protein kinase. TNF-α: tumor necrosis factor-α. IL: interleukin. Lox-1: lectin-type oxidized LDL receptor-1. MyD-88: myeloid differentiation primary response-88)
Fig. 4 The effects of statin on NLRP3 inflammasome and TLRs pathways. It appears that the effects of statins on NLRP3 complex are related to chemistry and pharmacokinetics features. Lipophilic statins have more pleiotropic effects on NLRP3 complex compare than hydrophilic statins. In the other hand, statins with inhibition of the mevalonate pathway, the protein prenylation or lipidation, and decreases cholesterol production caused reduce TLR agonists and suppressing TLR4/MyD88/NF-ĸB pathway. Also, statins inhibit NF-ĸB through reduce MAPKs phosphorylation and stabilized IKB-α as an NF-ĸB inhibitor. Statins inhibit expression of LOX-1 receptor; therefore, they could inhibit the inflammation of NLRP3 through LOX-1/NF-ĸB pathway. The diabetes basic risk, metabolic syndrome, genetic, and lifestyle could promote NLRP3 inflammasome in presence statins. The statin could decrease the expression of TLRs 2 and 4, so suppressed NF-ĸB activity. At the genetic and molecular level, the TLR4 D299G polymorphism contributes in less susceptibility to cardiovascular disorders and increase response to statin therapy; also, statin therapy has a positive effect on miRNAs levels which affected on TLRs and negatively regulated TLR4 (abbreviations: LDL: low-density lipoprotein. OXLDL: oxidized LDL. NLRP3: Is a NLRs. CCs: cholesterol crystals. NF-ĸB: nuclear factor kappa-light-chain-enhancer of activated B cells. Asc: apoptosis-associated speck-like protein containing a CARD. MAPKs: mitogen-activated protein kinase. TNF-α: tumor necrosis factor-α. IL: interleukin. Lox-1: lectin-type oxidized LDL receptor-1. MyD-88: myeloid differentiation primary response-88)CC BY · PubMed Central

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  1. Galea J, Armstrong J, Gadsdon P, Holden H, Francis SE, Holt CM (1996) Interleukin-1β in coronary arteries of patients with ischemic heart disease. Arterioscler Thromb Vasc Biol 16(8):1000–1006 · DOI

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Authors
Koushki, K., Shahbaz, S. K., Mashayekhi, K., Sadeghi, M., Zayeri, Z. D., Taba, M. Y., Banach, M., Al-Rasadi, K., Johnston, T. P., & Sahebkar, A.
Affiliations
  • Mashhad University of Medical Sciences (IR)
  • Ahvaz Jundishapur University of Medical Sciences (IR)
  • Medical University of Lodz (PL)
  • University of Missouri–Kansas City (US)
Corresponding author
Sahebkar, Amirhossein
ORCID
Venue
Clinical Reviews in Allergy & Immunology
Publisher
Springer Science and Business Media LLC
Published
2020-05-06
Volume
60
Issue
2
Pages
175-199
ISSN
  • 1080-0549 (ISSN-L)
  • 1559-0267
DOI
10.1007/s12016-020-08791-9
PMC
PMC7985098
OpenAlex
W3021399606
Cited by
382
References
216
Citations by year
2026: 50 · 2025: 74 · 2024: 70 · 2023: 86 · 2022: 52 · 2021: 40 · 2020: 9
FWCI
4.48
Type
journal article
Language
en
Open access
Licence
Locations
  • Clinical Reviews in Allergy & Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Polish Mother's Memorial Hospital Research Institute
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
Keywords
statins, atherosclerosis, NLRP3 inflammasome, Toll-like receptors, TLR4/MyD88/NF-κB signaling, IL-1β, IL-18, anti-inflammatory activity, hypolipidemic effect, dose-dependent effects, cardiovascular disease
MeSH terms
NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Anti-Inflammatory Agents, Cardiovascular Diseases, Humans, Signal Transduction, NF-kappa B, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Interleukin-18, Toll-Like Receptors, Interleukin-1beta, Inflammasomes

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